全文获取类型
收费全文 | 334篇 |
免费 | 20篇 |
出版年
2022年 | 6篇 |
2021年 | 11篇 |
2020年 | 4篇 |
2019年 | 6篇 |
2018年 | 8篇 |
2017年 | 12篇 |
2016年 | 9篇 |
2015年 | 19篇 |
2014年 | 19篇 |
2013年 | 36篇 |
2012年 | 26篇 |
2011年 | 23篇 |
2010年 | 13篇 |
2009年 | 19篇 |
2008年 | 24篇 |
2007年 | 14篇 |
2006年 | 12篇 |
2005年 | 15篇 |
2004年 | 10篇 |
2003年 | 3篇 |
2002年 | 8篇 |
2001年 | 4篇 |
2000年 | 6篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 2篇 |
1994年 | 2篇 |
1992年 | 4篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 4篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 3篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1976年 | 1篇 |
1974年 | 4篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1966年 | 2篇 |
1963年 | 1篇 |
排序方式: 共有354条查询结果,搜索用时 46 毫秒
101.
102.
Anita L. DeStefano L. Adrienne Cupples Kathleen S. Arnos J. H. Jr. Asher Clinton T. Baldwin Susan Blanton Melisa L. Carey Elias O. da Silva T. B. Friedman Jacquie Greenberg Anil K. Lalwani Aubrey Milunsky Walter E. Nance Arti Pandya Rajkumar S. Ramesar Andrew P. Read May Tassabejhi Edward R. Wilcox L. A. Farrer 《Human genetics》1998,102(5):499-506
Waardenburg syndrome (WS) type 1 is an autosomal dominant disorder characterized by sensorineural hearing loss, pigmentary
abnormalities of the eye, hair, and skin, and dystopia canthorum. The phenotype is variable and affected individuals may exhibit
only one or a combination of several of the associated features. To assess the relationship between phenotype and gene defect,
clinical and genotype data on 48 families (271 WS individuals) collected by members of the Waardenburg Consortium were pooled.
Forty-two unique mutations in the PAX3 gene, previously identified in these families, were grouped in five mutation categories: amino acid (AA) substitution in
the paired domain, AA substitution in the homeodomain, deletion of the Ser-Thr-Pro-rich region, deletion of the homeodomain
and the Ser-Thr-Pro-rich region, and deletion of the entire gene. These mutation classes are based on the structure of the
PAX3 gene and were chosen to group mutations predicted to have similar defects in the gene product. Association between mutation
class and the presence of hearing loss, eye pigment abnormality, skin hypopigmentation, or white forelock was evaluated using
generalized estimating equations, which allowed for incorporation of a correlation structure that accounts for potential similarity
among members of the same family. Odds for the presence of eye pigment abnormality, white forelock, and skin hypopigmentation
were 2, 8, and 5 times greater, respectively, for individuals with deletions of the homeodomain and the Pro-Ser-Thr-rich region
compared to individuals with an AA substitution in the homeodomain. Odds ratios that differ significantly from 1.0 for these
traits may indicate that the gene products resulting from different classes of mutations act differently in the expression
of WS. Although a suggestive association was detected for hearing loss with an odds ratio of 2.6 for AA substitution in the
paired domain compared with AA substitution in the homeodomain, this odds ratio did not differ significantly from 1.0.
Received: 27 July 1997 / Accepted: 9 December 1997 相似文献
103.
104.
105.
In a tropical nocturnal bird, the Indian spotted owlet, Athene brama, the intraperitonial injection of an identical amount (20 mg/100 g b. wt/day) of exogenous melatonin (MEL) for 15 consecutive days increased the pineal weight and plasma MEL level in sexually active birds while it decreased them in inactive birds more potently when injected in the evening (18.30-19.30 h) rather than the morning (0500-0600 h). On the other hand, more efficiently than the morning hour treatment, the evening hour MEL injection decreased the ovary weight and plasma estradiol and progesterone levels both in sexually active and inactive birds, but more potently in active than inactive birds. Thus, the exogenous MEL showed the time and reproductive phase dependent effects on the pineal gland and the ovary of this nocturnal bird. 相似文献
106.
Marquardt T Kostrewa D Balakrishnan R Gasperina A Kambach C Podjarny A Winkler FK Balendiran GK Li XD 《Journal of molecular biology》2005,354(2):304-316
Aldo-keto reductase AKR11C1 from Bacillus halodurans, a new member of aldo-keto reductase (AKR) family 11, has been characterized structurally and biochemically. The structures of the apo and NADPH bound form of AKR11C1 have been solved to 1.25 A and 1.3 A resolution, respectively. AKR11C1 possesses a novel non-aromatic stacking interaction of an arginine residue with the cofactor, which may favor release of the oxidized cofactor. Our biochemical studies have revealed an NADPH-dependent activity of AKR11C1 with 4-hydroxy-2,3-trans-nonenal (HNE). HNE is a cytotoxic lipid peroxidation product, and detoxification in alkaliphilic bacteria, such as B.halodurans, plays a crucial role in survival. AKR11C1 could thus be part of the detoxification system, which ensures the well being of the microorganism. The very poor activity of AKR11C1 on standard, small substrates such as benzaldehyde or DL-glyeraldehyde is consistent with the observed, very open active site lacking a binding pocket for these substrates. In contrast, modeling of HNE with its aldehyde function suitably positioned in the active site suggests that its elongated hydrophobic tail occupies a groove defined by hydrophobic side-chains. Multiple sequence alignment of AKR11C1 with the highly homologous iolS and YqkF proteins shows a high level of conservation in this putative substrate-binding site. We suggest that AKR11C1 is the first structurally characterized member of a new class of AKRs with specificity for substrates with long aliphatic tails. 相似文献
107.
Matusiak D Glover S Nathaniel R Matkowskyj K Yang J Benya RV 《American journal of physiology. Gastrointestinal and liver physiology》2005,288(4):G718-G728
Bombesin-like peptides are uniformly thought to act as mitogens in cancer. Yet by studying human tissues, we have recently shown that bombesin and its mammalian homologue gastrin-releasing peptide act as morphogens, promoting tumor differentiation when aberrantly upregulated in colon cancer. In contrast, little is known about the bombesin-like peptide neuromedin B (NMB) and its receptor (NMB-R) in the human gastrointestinal tract. We therefore studied their presence and function in normal and malignant human colonic epithelia. Anti-NMB monoclonal antibodies were made against keyhole limpet hemocyanin (KLH)-conjugated human NMB, whereas anti-NMB-R antibodies were raised in rabbits against KLH-conjugated peptides corresponding to the third intracellular loop and COOH-terminal tail of the receptor protein. NMB antibody recognized two bands at approximately 1.2 kDa and approximately 1.5 kDa. NMB-R antibodies recognized a band at 80 kDa (predicted 43 kDa); whereas treatment with the deglycosylating agent peptide-N-glycosidase generated bands at 65, 47, and 43 kDa. By immunohistochemistry, both NMB and NMB-R were expressed in normal and cancerous colonic epithelial tissues. In cancer, the amount of NMB was similar to that expressed by proliferating epithelial cells located within the crypt. In contrast, NMB-R expression was increased in cancer, with higher levels detected in better differentiated tumor cells. To assess NMB function, proliferation was determined in the nonmalignant human colonic epithelial cell line NCM-460 and in the colon cancer cell lines Caco-2 and HT-29. Exogenously added NMB was 50-100% more efficacious than gastrin-releasing peptide in causing tumor cell proliferation, whereas only NMB increased NCM-460 cell proliferation. These findings indicate that NMB and its receptor are coexpressed by proliferating cells in which they act in an autocrine fashion with similar and modest potency in both normal and malignant colonic epithelial cells. 相似文献
108.
Revathi Rajkumar Jheelam Banerjee Hima Bindu Gunturi R Trivedi VK Kashyap 《Genome biology》2005,6(2):1-23
Background
Phylogenetic analysis of human complete mitochondrial DNA sequences has largely contributed to resolving phylogenies and antiquity of different lineages belonging to the majorhaplogroups L, N and M (East-Asian lineages). In the absence of whole mtDNA sequence information of M lineages reported in India that exhibits highest diversity within the sub-continent, the present study was undertaken to provide a detailed analysis of this haplogroup to precisely characterize the lineages and unravel their intricate phylogeny.Results
The phylogenetic tree constructed from sequencing information of twenty four whole mtDNA genome revealed novel substitutions in the previously defined M2a and M6 lineages. The most striking feature of this phylogenetic tree is the formulation of a new lineage M30, distinguished by the presence of 12007 transition, and comprises of the recently defined M18 and a potential new sub-lineage possessing substitution at 16223 and 16300. M30 further branches into M30a sub-lineage, defined by 15431 and 195A substitution. The age of M30 lineage was estimated at 33,042 YBP, indicating a more recent expansion time than M2 (49,686 YBP). Contradictory to earlier reports, the M5 lineage does not always include a 12477 substitution, and is more appropriately defined by a transversion at 10986A. The phylogenetic tree also identifies a potential new lineage M* with HVSI sequence 16223,16325. No new substitutions were found in M25 and the M3 mt DNA genome could only be tentatively rooted by 16126 mutation. M4 and M*(16251, 16267) lineages could not be resolved distinctly.Conclusions
This study describes seven new basal mutations and fourteen lineages that substantially contribute to the present understanding of superhaplogroup M. The phylogenetic tree supported by median-joining network helps in distinctly identifying the genetic relation between different M lineages that could not be achieved solely by control region sequence information. Although high control region diversity has been reported in the different M lineages distributed in India, complete sequencing of M* and defined lineages suggests that these mt DNA genomes emerged from a limited number of branches arising from the M trunk. 相似文献109.
Rajkumar VS Howell K Csiszar K Denton CP Black CM Abraham DJ 《Arthritis research & therapy》2005,7(5):R1113-R1123
The mechanisms by which microvascular damage leads to dermal fibrosis in diffuse cutaneous systemic sclerosis (dcSSc) are
unclear. We hypothesized that microvascular pericytes constitute a cellular link between microvascular damage and fibrosis
by transdifferentiating into myofibroblasts. We used a combination of immunohistochemistry and double immunofluorescence labelling
of frozen skin biopsies taken from normal and dcSSc patients to determine whether a phenotypic link between pericytes and
myofibroblasts exists in dcSSc. Using α-smooth muscle actin, the ED-A splice variant of fibronectin (ED-A FN) and Thy-1 to
identify myofibroblasts, we demonstrated the presence of myofibroblasts in fibrotic dcSSc skin. Myofibroblasts were totally
absent from control skin, atrophic stage dcSSc skin and non-lesional skin. Using double immunofluorescence labelling, both
myofibroblasts and pericytes were shown to express ED-A FN and Thy-1 in dcSSc skin but not in control skin. Proliferating
cell nuclear antigen was also expressed by myofibroblasts and pericytes in dcSSc skin while being absent in control skin.
These observations suggest that the presence of myofibroblasts may represent a transitional phase during the fibrotic stages
of dcSSc and that Thy-1+ve pericytes participate in the fibrogenic development of dcSSc by synthesizing ED-A FN, which may be associated with a proliferation
and transition of pericytes and fibroblasts to myofibroblasts, thus linking microvascular damage and fibrosis. 相似文献
110.
The aim of this work was to study the mutation profile in hMSH2 and hMLH1 genes in hereditary nonpolyposis colorectal cancer (HNPCC) patients in India. On the basis of the Bethesda criteria, 31 colorectal cancer patients were studied first for microsatellite instability, using the five markers recommended by the Bethesda guidelines. Twelve of 31 tumor samples were found to be MSI-H, 9 of 31 were MSI-L, and the rest were MSS. The 12 patients with MSI-H were analyzed for mutations in hMSH2 and hMLH1 genes using PCR-denaturing high-performance liquid chromatography (dHPLC), followed by sequencing of samples showing abnormal peaks. Of the five mutations detected, three were found to be deleterious mutations (hMSH2-R680X, hMLH1-E671X, and a splice junction mutation IVS16-2A --> G); one had a mutation of probable significance (hMLH1-C680G) and one was of unknown significance (hMSH2-R171K). This study has also shown that most of the early-onset colon (4/7) and early-onset rectal (15/21) cancers are MSS or MSI-L. This is the first study to describe the mutation in hMSH2 and hMLH1 in Indian patients, a low incidence region for colorectal cancer. A two-stage procedure using MSI testing followed by PCR-dHPLC was found to be an efficient method in studying the mutation profile in high-risk patients. 相似文献